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Studies show positive results for biologics; investigators hunt for ways to create a healthy balance of gut bacteria
After many years of work, scientists are beginning to make substantial progress in understanding the causes of ulcerative colitis and Crohn’s disease, and developing more effective treatments. At least two new medications are nearing approval in the US and even more advances are moving through the research pipeline.
Lee Denson, MD, Director of the Schubert-Martin Inflammatory Bowel Disease Center at Cincinnati Children’s, summarized several of the most recent scientific advances in inflammatory bowel disease (IBD) at a family education day held March 2 in Mason, Ohio.
Currently, 130 clinical research studies involving people with IBD are active in the US, Denson says. Another 121 clinical studies are active in Europe and a few dozen other studies are happening in the rest of the world. Some of these projects are showing significant progress, especially projects involving biologics.
Tumor necrosis factor (TNF) plays a central role in IBD. Medications that are known to have anti-TNF effects include infliximab (Remicade), adalimumab (Humira), and certolizumab (Cimzia). Clinical trials of these biologic treatments have induced remission in up to 50% of patients.
Meanwhile, other studies are showing that early administration of anti-TNF therapy may be more effective than early immune modulator therapy at preventing the need for surgery.
However, clinicians cannot yet predict which patients will respond to anti-TNF therapy. More study also is needed to define which people may be most at risk of experiencing side effects that could include allergic reactions, infections, and possibly cancer, Denson says.
A recent pediatric comparative effectiveness study showed that, compared to early immune modulator therapy, early administration of anti TNF therapy led to higher rates of steroid- and surgery-free remission one year after diagnosis. This doesn’t mean that everyone should get anti-TNFα therapy, rather that we need to better define further characteristics of patients, such as genetics, serology, microbiome who will gain the most benefit. Confirmatory studies will be required.
This monoclonal antibody binds to integrin α4β7, an anti-adhesion molecule that is needed for recruiting the white cells that can trigger intestinal inflammation. Blocking integrin α4β7 has been shown to reduce inflammation in the intestine, which may help patients maintain remission, once achieved.
This therapy has shown positive results in Phase III clinical trials involving people with Crohn’s and ulcerative colitis. In fact, an FDA advisory committee has recommended approving this therapy for commercial use and final approval could happen this year, Denson says.
This drug, originally approved to treat psoriasis, appears to affect a molecular pathway that drives white cell activation in some patients. In a recent Phase III clinical trial, adults who did not respond to anti-TNF therapy did show improved symptoms when using ustekinumab. This treatment also is pending US FDA approval for people with Crohn’s disease.
Some studies are showing promising results from using the fecal bacteria of healthy donors to replace the defective gut microbiome of people with IBD and others with c.difficile infections. This filtered, diluted fecal preparation can be administered via enema, ND tube, endoscope and other methods. In an early-stage study, 15 of 24 people with IBD who tried this treatment achieved remission. Six current clinical trials are further exploring this approach.
Investigators have identified a NOD2 gene mutation that puts people with Crohn’s disease at higher risk of severe symptoms. People with the gene mutation and other serologic differences are more likely to develop early complications requiring surgery. The good news: there is now a commercial lab test available to detect these patients, which could help determine which patients are candidates for early interventions.
New genetic analyses are revealing that the mix of bacteria in the gut can vary considerably from person to person. By developing bacterial profiles, scientists are identifying IBD sub-types that may have higher clinical severity and lower remission rates.
As researchers learn more about the positive roles certain bacteria can play in the digestive system, interest in using probiotics as potential therapy has grown. Recently, work has begun to define a Microbial Dysbiosis Index which may guide the design of a probiotic specifically for people with IBD.
Scientists were hoping that secukinumab, a human anti-IL-17A monoclonal antibody, would be a beneficial treatment for moderate to severe Crohn's disease. But it turns out that IL-17A is needed to control bacteria growth in the gut. In a recent study that blocked IL-17A in 59 patients, 20 experienced infections, 30 percent of participants dropped out and some patients actually did worse than placebo.
Learn more about IBD-related clinical trials at Cincinnati Children’s
Lee Denson, MD
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